Cancers affecting the mucosae of the body are a growing public health concern. Oral cancer alone affects over 640,000 people annually worldwide and over 40,000 in the US. The incidence is on the rise due to an increased affliction with oral HPV, which is cancer causing. Treatment methods include surgery and systemic chemotherapy administered intravenously, often in combination. Surgery is often ineffective due to the difficulty associated with identifying margins surrounding oral tumors. This inability to completely remove tumors during surgery contributes to oral cancer's high rate of recurrence. Systemic chemotherapy is often used but lacks targeting and exposes the patient's entire body to damaging chemotherapeutics. This method can be dose limiting due to exposure within the blood stream and other organs, as precautions must be taken in consideration of the safety of this systemic exposure. Systemic delivery often results in damaging side effects from toxic drugs reacting with the body. These include neurotoxicity, nephrotoxicity, kidney failure, hair loss, nausea and mucositis.
In addition, oral cancer is among the most debilitating diseases emotionally as well as physically. Permanent disfiguration can occur after surgical resection of oral tumors. The patient's ability to eat, drink, or properly speak after surgery can also become impaired or not possible. In part for these reasons, oral cancer is considered the most expensive cancer to treat. The costs associated with surgery and chemotherapy themselves are substantially high. However, in the case of oral cancer there also are significant costs required to reconstruct the face, neck or other regions affected by the large removal of tissue. These can include jawbone or oral tissue reconstruction. Further, these procedures can also leave the patient hospitalized in recovery for long periods of time, which also contributes to substantial rehabilitative costs post-operation. These costs can add up to a sum that has been recognized as the highest costs associated with cancer, and can exceed the amount of US $150,000.
In addition to monetary cost and other physical side effects, emotional side effects also speak to the especially tragic and debilitating effect of oral cancer compared to other cancers and diseases. The emotional toll on oral cancer patients can be far greater than that of other diseases, primarily due to the physical deformity (including physical appearance and lack of clear speech) that results from treatment. The potential loss of significant portions of the tongue can be what leads to permanently impaired speech and even taste. The severity of this emotional effect can be fully understood when the suicide rates associated with other diseases are compared. The suicide rate of patients suffering from oral cancer is among the highest as compared to other cancers, and is about three times the rate of several other types of cancer. These consequences of traditional treatment methods for oral cancer illustrate why an alternative treatment method is desperately needed to address this unmet need and patient suffering.
Anal cancer accounts for 2.5 percentage of all digestive system malignances in the US, and approximately 8,000 new cases are diagnosed annually. The incidence of anal cancer in the general population has increased over the last 3 decades. Additionally, colorectal cancer (CRC) is a common and lethal disease. It is estimated that approximately 134,490 new cases of large bowel cancer are diagnosed annually in the US, including approximately 95,270 colon and 39,220 rectal cancers. This cancer remains the third most common cause of cancer death in the United States. Approximately 49,190 Americans are expected to die of large bowel cancer each year.
One of the differences between colorectal cancer and anal cancer are the risk factors that can cause each. Primary risk factors for colorectal cancer include age, genetics, race, diabetes, obesity, lack of exercise and smoking. In contrast, the primary cause of anal cancer has been the increase in prevalence of human papillomavirus (HPV).
As it pertains to anal cancer, almost all cases of anal cancer are caused by HPV, which is cancer causing, the presence of the HPV genome has been identified in 80%-85% of the cases of anal cancer. The HPV is able to live only in squamous epithelial cells that are found on the surface of the skin and on moist surfaces—mucosal surfaces. The virus is transmitted through skin contact. Sexual activity and other skin contact has been a primary driver of anal cancer. The primary driver of the rise in incidence is due to the rise of HPV. Smoking is another risk factor for anal cancer as it spreads carcinogens throughout the entire body and also reduces the immune system's ability to fight the HPV virus. Over 90% of anal cancer is squamous cell carcinoma, with the other 10% including more rare forms of cancer including basal cell carcinoma, adenocarcinoma, and malignant melanomas.
1. Anal Cancer Treatment:
Contrary to current perception, anal cancer is a very significant and debilitating disease. Treatment can include surgery, radiation, chemotherapy, and combinations thereof, often resulting in significant side effects. Despite the various choices, these treatment options remain ineffective in many cases at eliminating tumors and preventing death. As stated in the background, the percentage of patients surviving 5 years after treatment ranges between 45-85% according to the stage of the disease. The relatively low survival rate is unimpressive considering that anal cancer is typically discovered at early stages. According to US government statistics, 49% of anal cancer is localized at the time of diagnosis. An additional 31% exists regionally in the area; fewer than 20% are node-positive, while only 13% is discovered metastasized. The low 5 year survival rate despite these localized statistics suggests that current treatment options are not optimal and may be considered ineffective at treating anal cancer.
1.1 Surgery: While surgical treatment for anal cancer as the standard of care has since been replaced by chemotherapy, it is still used as a means of tumor reduction when chemotherapy shows little effect. This radical procedure can require the removal of the anus, rectum, and sigmoid colon, with creation of a permanent colostomy. An ostomy as it pertains to anal and rectal cancer is a surgically created opening in the abdominal wall that is used to divert bodily waste during and after anal surgery. For anal cancer, the most common ostomy is the colostomy. Instead of expulsion via the anus, feces and other waste pass through the opening of this and into an external collection bag. A specialized nurse is required to teach procedures regarding caring and washing of the ostomy and surrounding area. The process of surgically creating and personally maintaining the ostomy and collection bag can be very painful, emotionally challenging, can result in infection, and can be very expensive.
Developments of new strategies were directed at preservation of the anal sphincter. Surgery has been associated with local failure in up to half of cases, and five-year survival rates are approximately 50%-70%. In the past, surgical treatment with abdominoperineal resection (APR) (APR) was routinely performed for anal cancer. The radical procedure required removal of the ano-rectum with creation of a permanent colostomy. The overall probability of five-year survival was 40-70%, with a perioperative mortality of 3%. When surgery is used, side effects are extensive and debilitating. The most common immediate complication (in 32% of patients) is intra-abdominal or pelvic abscess, other complications include nerve injury (the autonomic nerves that affect both sexual and urinary function may be injured), postoperative sexual or urinary dysfunction (10-60%), urologic injury, perineal wound, and complications related to the ostomy. Current treatment approaches reserve surgical therapy for patients with recurrent or persistent disease after chemoradiotherapy. Although prognosis is poor overall, an APR offers the potential for long-term survival. Local excision is performed by several surgeons for small, local perianal cancer, where sphincter function will not be compromised by adequate surgical resection.
As mentioned before, in more serious (refractory or recurrent) cases of anal cancer, APR is performed, in these cases, a permanent colostomy is needed, and permanent damaging side effects are common. Failure to control anal cancer and complications of treatment are alternative indications for a colostomy, but in most cases, colostomy is required for recurrent tumor.
1.2 Chemotherapy: Systemic chemotherapy is often used but lacks targeting and exposes the patient's entire body to damaging chemotherapeutics. This method can be dose limiting due to exposure within the blood stream and other organs, as precautions must be taken in consideration of the safety of this systemic exposure. Systemic delivery often results in damaging side effects from toxic drugs reacting with the body. These include neurotoxicity, nephrotoxicity, kidney failure, hair loss, nausea and mucositis. As an alternative to surgery, chemotherapy in addition to radiation are also used as methods to treat anal tumors. The current standard of care uses initial concurrent combination of chemotherapy and radiation for patients with anal canal squamous cell carcinoma, even with small, local tumors. When chemotherapy is used, temporary central venous catheters or peripherally inserted central catheters may be used on an individual. Side effects from treatment include those typical to systemic chemotherapy. These include nausea, hair loss, kidney damage, low blood cell count, mouth sores and a compromised immune system. Since chemotherapy is currently delivered systemically throughout the body, there are dose limiting factors which can result in lower dosages being administered than what is considered optimal.
1.3 Radiation: Forms of radiation administered include external radiation or brachytherapy (internal radiotherapy, aiming to spare the surrounding normal structures). These can be used as a treatment method in combination with chemotherapy, and are very extensive. They are commonly administered 5 days a week for 5 to 6 weeks. In addition to the side effects, this high frequency of administration contributes to the strenuous nature of this treatment method. Side effects can persist post-treatment and include irritation, pain during bowel movements and urination, vaginal pain or vaginal stenosis (for women) and erectile dysfunction or impotence (for men). Sexual and gastrointestinal dysfunction can occur and will often last throughout the remainder of the patients' life. The incidence of late toxicity from radiation such as anal ulcers, stenosis, and necrosis, is also dose-dependent.
2. Rectal Cancer Treatment:
2.1. Surgery: Different surgical options are available, according to the stage, location, differentiation of the tumor. Superficially invasive, small rectal cancers managed with limited surgical procedure—trans-anal excision (TAE). Disadvantages of TAE alone are the high recurrence rate (up to 31%), potential compromise for cure, and the need for additional wider resection when positive to cancer margins are found. Since the majority of patients have more deeply invasive tumors, more extensive surgery is required, surgical options include total mesorectal excision (TME), low anterior resection (LAR) that includes rectum and sigmoid colon removal.
These surgical options carry a variety of complications including risk of perioperative mortality. Wound infections, fecal frequency or urgency, the need for rectal reconstruction with its complications, anastomosis leak that leads to considerably high rates of morbidity and possible mortality. Patients also risk functional derangements or, even, incontinence. Sexual and bladder function may also be adversely affected, probably because of injury to autonomic nerves.
The last surgical option is the abdominoperineal resection (APR) with its potential complications (mentioned above).
2.2 Radiotherapy: radiotherapy combined with chemotherapy can be used as a neoadjuvant (induction chemoradiotherapy) can be used for locally advanced or node-positive tumors, adjuvant treatment aims to improve local control and survival, and reduce recurrence.
2.3 Chemotherapy: As mentioned before, chemotherapy is used in combination with radiation as part of neoadjuvant or adjuvant treatment. The regimen of chemotherapy used is typically FOLFOX (5-FU, leucovorin, and oxaliplatin) or CapeOx (capecitabine and oxaliplatin). These chemotherapies are given systemically leading to systemic toxicities as mentioned prior.
Anal and rectal cancer together account for a very significant portion of cancer cases within the United States and worldwide, however due in part to the side effects and limited efficacy described above, still lack an ideal safe and effective treatment option. In order to address this severe unmet need, provided herein is an alternative, more effective treatment option for colorectal and anal diseases. Agents commonly delivered in large doses systemically to treat these conditions have been reformulated for localized delivery and retention, resulting in higher local concentration of agents while a lower overall dosage has been administered. The present invention aims to overcome the shortcomings, side effects, and lack of efficacy of current treatment options.
Difficulties in delivering therapeutic agents to mucosal tissues can also be a hurdle to the treatment of diseases affecting the gastrointestinal (GI) tract. For example, over three million people are diagnosed with C. difficile colitis each year in the United States alone, and such disease can be caused by antibiotics which destroy the body's natural bacteria. GI diseases, including inflammation, IBD and its variants can also stem from malnutrition, unsanitary living conditions, exposure to bacteria, and other causes. These causes explain a significantly higher prevalence in developing nations, particularly those in Africa and Southeast Asia. Children under five years of age are particularly vulnerable to these conditions. There exists substantial risk of life-threatening complications such as dehydration, sepsis, kidney failure, colon perforation, and death. These are diseases of a very debilitating, painful and widespread nature and represent a chronically underserved market.
Despite the drawbacks of traditional drug administration routes, they remain effective in certain cases at releasing therapeutic, diagnostic and/or prophylactic agents into the gastrointestinal tract. However, when employing these routes, local delivery of agents not only within the intestine but also through the intestinal mucosa remains very difficult. The mucosa layer on the intestinal wall presents a formidable barrier to adhesion and absorption of such agents, such as biologics, peptides, pharmaceuticals and nutraceuticals which are commonly delivered in standalone forms. Few compositions can penetrate this viscous, slippery material to reach the tissue and cells beneath.
Pertaining to targeted delivery, it is difficult for most substances to become attracted to these cells long enough to deliver an effective amount of the therapeutic, diagnostic and/or prophylactic agent. This remains one of the principal difficulties limiting the efficacy of treatments delivered to the GI tract. Likewise, sufficient targeting to regions within the GI tract remains highly difficult due to the complex makeup of the GI tract. Highly acidic levels within the stomach and varying pH levels within different sectors of the intestine contribute to targeting difficulty, particularly to particle-based therapies. For example, the pH of the duodenum of a fasted patient can be approximately 4.5 while the jejunum exhibits a pH closer to 6.5. A delivery system would in this example have to be able to withstand the stomach pH (1.5-2.5) in addition to the pH of the duodenum in order to be delivered into the jejunum. This scenario is present across the GI tract depending on the region and fed vs. fasted condition of the patient.